Antisense Oligonucleotide Silencing for HNRNPH2 and PCDH19 Disorders
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Solution Overview
Problem
Current methods are inadequate for treating X-linked genetic diseases caused by mutations in HNRNPH2 and PCDH19, which result in neurodevelopmental disorders such as MRXSB and EIEE-9, characterized by developmental and intellectual retardation, muscle hypotonia, autism spectrum disorders, and severe epileptic seizures, due to the mixed expression of wild-type and mutant proteins in females and mosaic expression in males.
Innovation Solution
Administering antisense oligonucleotides that specifically bind to and downregulate the expression of HNRNPH2 or PCDH19 mRNA, reducing the expression of both wild-type and mutant forms without affecting HNRNPH1 or other genes, thereby modulating splicing and reducing protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatment methods are used for X-linked genetic diseases, then general symptom management is possible, but the underlying cause of neurodevelopmental disorders cannot be effectively addressed due to mixed expression of wild-type and mutant proteins
Solution Approach 1:
The treatment targets specific mRNA transcripts (HNRNPH2 or PCDH19) separately from other similar genes, using segmented antisense oligonucleotide sequences that bind only to the disease-causing gene's mRNA while leaving related genes (like HNRNPH1) unaffected. This segmentation allows precise treatment of the mutant protein expression without disrupting normal protein function from other genes.
Solution Approach 2:
The invention changes the molecular parameter of gene expression by introducing antisense oligonucleotides that bind to mRNA, preventing translation and thereby altering the quantity of protein produced. This parameter change (from normal expression to downregulated expression) directly addresses the root cause of the disorder by reducing mutant protein levels while preserving wild-type protein function through selective binding.
2Measurement precision
If antisense oligonucleotides are designed to bind to HNRNPH2 mRNA, then specific downregulation of HNRNPH2 expression is achieved, but there is a risk of off-target binding to HNRNPH1 mRNA
Solution Approach 1:
The antisense oligonucleotide sequence is designed with local quality differences - specific nucleotide variations at critical binding positions that create high affinity for HNRNPH2 mRNA while maintaining low affinity for HNRNPH1 mRNA. This local differentiation in binding characteristics ensures selective downregulation of HNRNPH2 without affecting HNRNPH1 expression, eliminating off-target effects.
3Adaptability or versatility
If X inactivation or mosaic expression is allowed to proceed naturally, then genetic diversity is maintained, but a mixture of cells with intact and mutated protein creates neurological phenotype
Solution Approach 1:
The invention converts the harmful effect of mixed cell populations (some producing mutant protein, others producing wild-type protein) into a beneficial therapeutic outcome by using antisense oligonucleotides to selectively eliminate the mutant protein's harmful effects. The oligonucleotides bind to and downregulate both wild-type and mutant HNRNPH2 or PCDH19 mRNA, thereby removing the source of neurological damage while preserving genetic diversity in the population.
Data Source
AI summary
Methods of treating a neurodevelopmental disorder caused by a mutation in HNRNPH2 or PCDH19, comprising downregulating expression of HNRNPH2 or PCDH19 in cells of the brain of a subject are provided. Antisense oligonucleotides useful in performing the methods of the invention are also provided.